An Ounce of Prevention: Controlling Chemotherapy-Induced Nausea and Vomiting

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Among the most common and difficult side effects of cancer treatment is chemotherapy-induced nausea and vomiting (sometimes referred to as CINV). It's serious business because vomiting can lead to dehydration and malnutrition and ultimately delay the completion of chemotherapy. Learn more about the causes of nausea and vomiting related to chemotherapy, and the most up-to-date prevention and treatment strategies, in this interview with medical oncologist Dr. Frankie Holmes of US Oncology.

This program was produced by HealthTalk and supported through an unrestricted educational grant from MGI Pharma.

Announcer:Welcome to this HealthTalk program, An Ounce of Prevention: Controlling Chemotherapy-Induced Nausea and Vomiting. Support is provided to HealthTalk through an unrestricted educational grant from MGI Pharma. We thank them for their commitment to patient education. The opinions expressed on this program are solely the views of our guests. They are not necessarily the views of HealthTalk, our sponsor or any outside organization. And, as always, please consult your own physician for the medical advice most appropriate for you. Now, here's your host, Jeanne-Marie Maher.

Dr. Jeanne-Marie Maher:Hello and welcome. I'm Jeanne-Marie Maher. Today we are going to discuss one of the most dreaded side effects of chemotherapy - nausea and vomiting. Not only do patients fear it, but if it's serious enough it can actually delay cancer treatment in some cases. And once a person experiences that unsettling feeling of queasiness, it can be extremely difficult to bring it under control.

Our guest, Dr. Frankie Ann Holmes, is here to talk about newer treatments and strategies that may allow you to control and even prevent chemotherapy-induced nausea and vomiting [also referred to as CINV]. Dr. Holmes is a medical oncologist with Texas Oncology in Houston, where she treats breast cancer patients. She is also an active member of the Breast Medical Oncology Committee of the US Oncology research network. Welcome to the program, Dr. Holmes.

Dr. Frankie Holmes:I am so happy to be here, especially to talk about a subject which makes a great deal of difference for our patients to allow them to get their life-saving chemotherapy.

Dr. Maher:Let's begin by defining our terms. There are three types of chemotherapy-induced nausea and vomiting - anticipatory, acute and delayed. Would you explain the differences in those categories, Dr. Holmes?

Dr. Holmes:
Anticipatory nausea and vomiting is a learned response. This occurs because a response is associated with a specific stimulus or situation. In the case of chemotherapy, the patient receives chemotherapy, has [acute nausea and] vomiting, and therefore in the future they anticipate that they may vomit and because of that anticipation, they vomit even before they receive the chemotherapy.

Acute nausea and vomiting occurs between hours zero and 24 after receiving chemotherapy. Delayed nausea and vomiting occurs two to five days after receiving chemotherapy.

We know that there are specific differences in these three types of nausea and vomiting because there are different ways of controlling it. For example, with anticipatory nausea and vomiting we can use benzodiazepines such as lorazepam, or Ativan, and Valium [diazepam] that can prevent the anxiety that can lessen the anticipation of the nausea and vomiting.

Acute nausea and vomiting is caused by the release of serotonin from specific cells in the intestines, and we have specific drugs, the 5HT3 receptor antagonists, the so-called setrons [serotonin antagonists] that can block this response. The delayed nausea and vomiting, which occurs two to five days after treatment but which in some studies may occur as early as 16 hours after the chemotherapy, is caused by a [different] chemical called substance P, and a specific treatment for this has recently been developed, [called] aprepitant [Emend].

Dr. Maher:
Does everyone who gets chemotherapy suffer from nausea and vomiting?

Dr. Holmes:Fortunately not. The causes of nausea and vomiting are, first, related to the emetogenic [vomit inducing] intensity of the chemotherapy - that is, how strong is the stimulus? And we have a grading system for that. Secondly, it relates to the personality profile of the patient in terms of how their body handles certain drugs. For example, it's been shown that women are more likely to vomit than men. Thin women are more likely to vomit than heavier women. Women who do not smoke and who do not drink alcohol, that is, who have less chemical input into their body that needs to be metabolized, are also more likely to have nausea and vomiting. And of course, as we indicated in our definition of anticipatory nausea and vomiting, women who have had a vomiting episode before with chemotherapy are more likely to vomit.

There are a few other conditions that make patients more likely to vomit. Women who have significant vomiting with pregnancy are also likely to have more vomiting with chemotherapy. And finally, women who have car sickness and women who tend to vomit easily for other reasons will also tend to vomit more with chemotherapy.

Dr. Maher:
For those who don't know what emetogenic means, can you describe what that means specifically?

Dr. Holmes:
Emetogenic comes from the word emesis. Emesis is the word for vomiting, and emetogenic means causing nausea and vomiting.

Dr. Maher:Are there patients who are less likely to experience chemotherapy-induced nausea and vomiting?

Dr. Holmes:Yes. These would be the patients who are receiving [chemotherapy] drugs that do not cause as much nausea and vomiting, men, patients who smoke and drink, patients who are heavier, and patients who have had a previous good experience with chemotherapy.

Dr. Maher:Could we talk about the factors that contribute to nausea and vomiting during chemotherapy? Let's start with the drugs and then talk about the physical causes of nausea and vomiting. We know that all chemotherapy is not equal when it comes to these distressing symptoms. In fact, chemotherapy drugs are classified according to how likely they are to cause nausea and vomiting. Can you tell us about each of these classifications and some of the drugs that fit in them?

Dr. Holmes:The most commonly accepted and the easiest to remember classification of nausea and vomiting is the one that I call HEC, MEC, LEC and mini-MEC. HEC stands for highly emetogenic chemotherapy, and this includes drugs like cisplatin [Platinol] in doses of greater than 60 milligrams per meter squared; DTIC [dacarbazine] or nitrogen mustard. These drugs cause vomiting in 100 percent of patients who do not have any prophylactic medications.

In terms of moderately emetogenic chemotherapy, or MEC, these are drugs like Adriamycin, or doxorubicin, in doses of greater than 50 milligram per meter squared, carboplatin [Paraplatin], Cytoxan [cyclophosphamide]. These cause nausea and vomiting in about 30 to 70 percent of patients who do not receive prophylactic or preventative medication.

Then there are lower levels of emesis, LEC. These consist of the taxanes [paclitaxel (Taxol) and docetaxel (Taxotere)], and these may cause nausea and vomiting in about 10 to 30 percent of patients. Then there is [are] minimally emetogenic drugs like Navelbine [vinorelbine], Fludara [fludarabine], or fluorouracil, also called 5-FU.

Dr. Maher:Now that we've clarified how chemotherapy drugs differ in their tendency to cause nausea and vomiting, let's talk about what actually happens in the body to cause these symptoms. It's a complex process, isn't it, Dr. Holmes?

Dr. Holmes:You're absolutely right, and one of the exciting things is that the more we understand about how this works, then we can find the specific points in these cycles where we can intervene. For example, for acute nausea and vomiting, we've found that in the intestinal tract, from the stomach all the way down through the colon, there are special cells called enterochromaffin cells, and we can think of them as the early warning system of the intestines. Their job is to detect harmful substances in the body, in the blood, in the intestinal tract, and in response to that, they release serotonin. This serotonin travels across to the intestines to land, or dock, with a special receptor called the 5HT3 receptor. When that serotonin docks, or links up with its receptor, it then sends a signal up through the nerves of the intestine to the spinal cord up to the brain to the vomiting center and the chemotherapy trigger zone to initiate the muscular and other events that cause vomiting. We have discovered that in acute nausea and vomiting, the link that we can target is the 5HT3, the serotonin receptor in the gut, and that's where our most powerful and our platinum standards, the "setrons," or the 5HT3 receptor antagonists, work.

Now, the second type of nausea and vomiting that we talked about, delayed nausea and vomiting, is related to a chemical called substance P, and that binds to an area in the brain which has NK receptors. When substance P binds to those NK receptors, it also initiates the cascade of events that causes nausea and vomiting. Fortunately, there is a new medication called aprepitant, or Emend, that blocks these receptors and can prevent this cascade of nausea and vomiting.

Dr. Maher:When you refer to the gut, Dr. Holmes, are you talking about the entire digestive system or are you just talking about the stomach?

Dr. Holmes:When we speak about the gut, and that's a very important point, these serotonin receptors are present from the stomach all the way to the colon.

Dr. Maher:
Could we talk about the management of symptoms? Could you explain why it's important to treat nausea and vomiting in a person getting chemotherapy, beyond the obvious reason, that these are very unpleasant symptoms.

Dr. Holmes:It's very important to prevent nausea and vomiting, not just because none of us would want to undergo that ourselves, but because studies have shown that for many patients, nausea and vomiting, or the fear of it, is a reason to avoid chemotherapy entirely. Chemotherapy treatments can be curative in instances of breast cancer or lymphoma or even with some of the other malignancies such as colon cancer. We can't let these side effects prevent life-saving treatments for patients.

Secondly, nausea and vomiting will also cause dehydration. It can cause electrolyte abnormalities. For patients who have heart problems who are on specific medications, if their electrolytes become unbalanced, we can end up with complications related to interactions with their existing drugs. It can cause weight loss. Weight loss means that patients will not be able to tolerate the chemotherapy as well. Of course there's nothing harder than trying to do your normal life, to love your children, to deal with the frustrations of your family life, to try and perform your job so you can keep your health insurance so you can continue to get your treatment, when you feel nauseated. It is a terrible impediment to quality of life.

Finally, to emphasize again the whole notion about delaying chemotherapy treatment, study after study has shown that when patients fear nausea and vomiting, they may not return for additional chemotherapy treatments. This cannot only be difficult in the short term, it can prevent them from being cured of their cancers.

Dr. Maher:
I know there are numerous treatments for nausea and vomiting, associated with chemo, can you describe them and tell us which ones work best for each of the three types of nausea and vomiting?

Dr. Holmes:
First off, anticipatory nausea and vomiting is this learned response, and there [are] two very effective treatments for that. The first is not to get nausea and vomiting. So if we can do a good job at preventing acute and delayed nausea and vomiting, then we won't have to deal with anticipatory nausea and vomiting. However, even for patients who have never had chemotherapy but they've heard about it, there is a certain anxiety level. For that anxiety, the benzodiazepines, such as lorazepam, or Ativan, Valium [diazepam], or similar medications are quite effective. These must be started before the patient receives treatment with their chemotherapy, and, in many cases, patients have to receive these even before they come to see the doctor to break that cycle. The other important thing about these kinds of medications [the benzodiazepines] is sometimes they induce a mild degree of memory loss, short-term, so if there is a problem with nausea and vomiting, patients won't remember it, and therefore it won't be part of the stored baggage that will cause anticipatory nausea and vomiting the next time around.

For acute nausea and vomiting, the gold standard has really become these 5HT3 receptor antagonists that are called the setrons. These include Zofran [ondansetron], Anzemet [dolasetron] and Kytril [granisetron]. These are the standards developed in the 1980s. These can all be given IV or orally. They are all thought to be equivalent, although more recent scrutiny of these medications indicates that there are some differences in regards to their effects on the heart.

Up until now, these were considered the state-of-the-art treatment. Recently, a new medication in this same family called palonosetron, or Aloxi, has been developed, and this is a second generation of this same family of 5HT3 receptor antagonists. It has advantages in having a much longer half-life - 40 hours compared, for example, with only four hours with ondansetron [Zofran] or approximately 10 hours with Kytril, or about 7½ hours with Anzemet. It [Aloxi] is also much more potent milligram per milligram. For example, the dose of Aloxi is 0.25 milligrams whereas we're routinely giving 100 milligrams of Anzemet or 32 milligrams of Zofran. It [Aloxi] binds to the 5HT3 receptor much more tightly, so it doesn't tend to disengage from the receptor as easily as the other drugs. The most important of all of these properties is the long half-life, which allows it to be connected to that receptor for almost 48 hours.

The second type of treatment is a new product that blocks substance P, and this is called aprepitant, or Emend. This is only given as an oral medication in contrast to the 5HT3 receptor antagonists that are given as oral or IV. The aprepitant is usually given as a larger dose on day one, 125 milligrams, and on days two and three as a smaller dose of 80 milligrams. It's important to know that aprepitant must be given with two other medications, or it will not be effective. It must be given with dexamethasone [a steroid], and the usual dose for highly emetogenic chemotherapy is 12 milligrams of dexamethasone and for moderately emetogenic chemotherapy it's 8 milligrams. On the second and third days, dexamethasone must be continued in order for the Emend to also be effective. The other important medicine that is critical to be given with Emend to allow it to work is one of the 5HT3 receptor antagonists - Kytril, Anzemet or Zofran. Without this 5HT3 receptor antagonist, the Emend will not provide any acute coverage for nausea and vomiting, and the amount of delayed nausea and vomiting coverage is also lessened, so we have to use three drugs when we use Emend.

Other treatments for nausea and vomiting that have been used in the past are directed at the pathways of nausea and vomiting. For example, we have known about dopamine pathway blockers, and these include some of the older drugs like Haldol [haloperidol], Reglan or metoclopramide, can be useful. We know that the cannabinoids like the marijuana-equivalent tablets [Marinol (dronabinol)] can also be useful for emesis [vomiting]. It has recently been shown that gamma-aminobutyric acid, or GABA, is another pathway that can lead to emesis. And there was one report in Lancet [a British medical journal] about the use of Neurontin [gabapentin], which is one of the drugs we commonly employ for hot flashes and for neuropathic pain in our cancer patients that showed this also prevented nausea and vomiting. Histamine-related pathways are another method that can be used to block emesis, and this includes drugs like Benadryl [diphenhydramine].

Dr. Maher:I'd like to ask you a little more about the newer drugs, Aloxi and Emend. We know most medications have some side effects - what about these?

Dr. Holmes:
The side effects of Aloxi are very consistent with the side effects that we have become very comfortable with in the 5HT3 receptor antagonists, Kytril, Zofran and Anzemet, and this includes some headache, constipation. Some patients have a little bit of dizziness. These side effects are very infrequent and occur in less than 5 percent of patients.

With Emend, the side effects are a little bit different. In addition to the constipation that may occur and the headache that we have come to expect, it may cause a little bit more fatigue. It was up to about 18 percent in one study. It may also cause hiccups. I haven't seen hiccups in any patients, but in one of the trials it caused an 11 percent incidence of hiccups, and this was compared to a 6 percent incidence with standard treatments. All anti-emetics can cause a degree of anorexia - decreased appetite - but there are other factors that may be related to that.

Aprepitant [Emend] does require a little more attention in administration of other drugs because it will increase metabolism of [certain] drugs. The Decadron [dexamethasone] dose that we use is lesser when we give aprepitant because it will delay metabolism of the Decadron, and we don't need to give us much. Emend will also increase the metabolism of Coumadin (warfarin, an anti blood-clotting drug); so if patients were to take it [Emend] for longer than three days that would be something to be concerned about. But Emend is given only for three days, so in actual practice, these concerns don't tend to be of significant clinical consequence.

Dr. Maher:Just to be clear, are Aloxi and Emend used to prevent chemotherapy-induced nausea and vomiting?

Dr. Holmes:
Aloxi and Emend are wonderful additions to our arsenal of agents to prevent nausea and vomiting, and in their own way they provide very novel mechanisms that have specific advantages for our patients. For example, Aloxi has such a long half-life that patients get one injection at the time they get their chemotherapy and they do not need to take any additional 5HT3 receptor antagonists. In the past, we've often sent our patients home with some samples of Zofran, etc. Those drugs will not add anything to Aloxi. After they leave our offices, they may need to take some of the other adjunctive medicines such as lorazepam [Ativan] [or] Reglan [metoclopramide], and they may take their Emend, but they don't need to take any more of these 5HT3 receptor antagonists.

Emend, for patients who have highly emetogenic chemotherapy, which is the FDA indication, have excellent results in terms of prevention of nausea and vomiting. For many of us who don't use a lot of highly emetogenic chemotherapy, there was a study published at ASCO (American Society of Clinical Oncology) showing that Emend was very effective in moderately emetogenic chemotherapy. This is not yet an approved indication, but it has been shown to be effective in this situation.

That [ASCO] is the organization to which most American oncologists belong, and that organization sets standards for patient care. It is very likely that when the supportive care committee of the American Society of Clinical Oncology meets again in the future, they will be recommending the use of aprepitant for these patients who receive moderately emetogenic chemotherapy.

There are some drugs, and doxorubicin [Adriamycin] is one of them, that have both acute and delayed nausea and vomiting. For those patients who receive moderately emetogenic chemotherapy with doxorubicin who have delayed nausea and vomiting, it makes perfect sense to use aprepitant in that situation. I might also add that the National Comprehensive Cancer Center Network, the NCCN, also has guidelines for anti-emetic use. You can get them at www.NCCN.org. Their guidelines for emesis control include the use of Aloxi as the first line for prevention of nausea and vomiting instead of the first-generation 5HT3 receptor antagonists such as Zofran, Kytril and Anzemet.

Dr. Maher:It sounds like with Aloxi and Emend we've added two more effective additions to our armamentaria of [treatments for] chemotherapy-induced nausea and vomiting. Are you aware of any other treatments that are in development for these symptoms?

Dr. Holmes:We are constantly learning about the pathways of nausea and vomiting and the more we know about the problem, the more we know about the enemy and the weak links, we will be able to develop new drugs. One interesting study that I read about helped us understand that there are patients who do not respond to these 5HT3 receptor antagonists, and the reason is that the receptor is mutated. The receptor is the protein that [sets] on the surface of the cell in the intestines or in the gut and is waiting for the serotonin to activate it, so it can send a single to the vomiting centers. However, there are patients who have a deformed receptor, so when that 5HT3 receptor antagonist goes in to block that pocket, the pocket can't be completely blocked because it's abnormally formed. It's just like the space shuttle - you have to get a square peg in a square hole. Well, what if they cheat, now they have an octagonal hole, there are some places that aren't blocked, and the serotonin can then get in and activate that receptor.

We have come to learn that we're all so wonderfully, uniquely differently, and the enzymes that metabolize these drugs may be present in greater or lesser amounts in each of us. About 2 percent of our population are called ultrarapid metabolizers. That means they break them [these drugs] down much more quickly than the average. They can tell this because when they do a gene analysis of the number of genes that are necessary to metabolize these drugs, these patients may have three or more copies of these genes. These patients will need a higher dose than the average person because the drug is more rapidly broken down and made inactive. In the future, we will undoubtedly be doing genomic profiling of our patients to determine if you are an ultrarapid metabolizer.

Dr. Maher:
Could you give our audience some practical tips, such as what a patient might do to minimize their risk of nausea and vomiting during chemotherapy?

Dr. Holmes:The most important thing that we would say to a patient is science is out there. We have wonderful ways of treating and preventing nausea and vomiting, so give us a chance. Don't remember what you saw on television or the movies or even what you've heard. You're a unique patient, and have confidence that we will be able to take care of your nausea and vomiting. That's the first thing. Come with hope.

A few practical things: Don't go to your chemotherapy treatment without eating. Now, we don't want you to have bacon and eggs and sausage, but have something light, some toast and jelly, perhaps some cereal. Secondly, don't take agents that we know are hard on the stomach, and this includes alcohol, some of the pain relievers such as aspirin or Motrin, Advil [ibuprofen] - the nonsteroidals. The third thing is, if you know that you are an anxious person, mention that to your doctor and he [or she] will likely be very comfortable recommending that you take some Ativan or something to minimize your anxiety.

A final thing that will help us is try and keep a record of what your experience with chemotherapy is. If you do get nausea and vomiting, when do you get it? If you get nausea and vomiting later on, is there anything that may have triggered it? We often find that patients may have a little bit of gastroesophageal reflux, acid indigestion, and that's not normally a problem but when they get on chemotherapy, that becomes more of a problem and causes nausea and vomiting. So a lot of patients have their nausea and vomiting prevented by getting on some medications their doctor may give such as Prilosec [omeprazole] or even Pepcid AC over-the-counter.

Dr. Maher:Dr. Holmes, thank you so much for joining us. We've been discussing the prevention and treatment of chemotherapy-induced nausea and vomiting with Dr. Frankie Ann Holmes of Texas Oncology in Houston. From our studios in Seattle and all of us in HealthTalk's Cancer Education Networks, we wish you and your families the best of health.

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